bardoxolone methyl (RTA 402) / Kyowa Kirin, Biogen - LARVOL DELTA

Effect of bardoxolone methyl on the lower reproductive tract microbiome in turkey breeder hens. (PubMed, Front Physiol) - "These findings indicate that bardoxolone methyl treatment can finetune microbial functional capacity without destabilizing overall community structure. The results also highlight the importance of considering tissue-specific differences and functional potential when investigating reproductive function."

Journal • Infertility • Inflammation

Rodent-specific induction of cholestasis and cholangioma through the reduction of bile salt export pump by bardoxolone methyl. (PubMed, J Toxicol Sci) - "These results strongly suggest that the effects of bardoxolone methyl on the hepatobiliary system differ among animal species, especially between rodents and non-rodents. In conclusion, the risk of cholestasis and cholestasis-derived carcinogenicity associated with bardoxolone methyl are expected to be quite low in humans."

Journal • Preclinical • Biliary Cancer • Cholangiocarcinoma • Cholestasis • Hepatology • Liver Failure • Oncology • Solid Tumor

Bardoxolone methyl (Bard)-mediated strong suppression of calcium oxalate crystal formation in renal crystal recurrence model. (PubMed, Sci Rep) - "Preadministration of bardoxolone methyl (Bard), a potent Nrf2 activator, significantly suppressed recurrent CaOx crystal formation. These findings strongly suggest the existence of an interaction between oxidative stress responses and renal crystal recurrence, highlighting the potential of Nrf2 activation as a preventive strategy for recurrent stone formation."

Journal

Bardoxolone methyl triggers Ferroptosis in cardiomyocytes. (PubMed, Hum Exp Toxicol) - "Mechanistically, Bardo suppressed SLC7A11 and GPX4 expression while elevating ROS, ferrous ions, and MDA levels. Ultrastructural analysis further revealed mitochondrial volume reduction, disrupted cristae, and increased membrane density.DiscussionThese findings establish that Bardo induces ferroptosis in cardiomyocytes, potentially explaining the cardiotoxic effects observed in clinical trials."

Journal • Cardiovascular • Diabetic Nephropathy • Nephrology • Renal Disease • GPX4 • HMOX1 • NQO1 • SLC7A11

Role of Nitric Oxide and Nrf2 to Counteract Vascular Endothelial Dysfunction Induced by Periodontal Pathogens Using HUVECs. (PubMed, Cells) - "Treatments with L-Sepiapterin and CDDO-Me restored NO bioavailability, reduced oxidative and inflammatory responses, normalized metabolic gene expression, and attenuated apoptosis, with CDDO-Me showing more promising effects. This study provides the mechanistic insight linking periodontal polybacterial infection to endothelial dysfunction and metabolic impairment such as diabetes, suggesting that redox-modulating strategies such as L-Sepiapterin and CDDO-Me may help prevent vascular damage associated with periodontal disease."

Journal • Dental Disorders • Diabetes • Infectious Disease • Inflammation • Metabolic Disorders • Periodontitis • TLR4

Optical pooled screens identify activation of NRF2 as a novel therapeutic target in ALS/FTD (ALS-MND 2025) - "We next applied antisense oligonucleotides targeting KEAP1 and UBE2M, and small molecules, including bardoxolone-methyl, to activate NRF2. OPS in FUS-P525L patient-derived fibroblasts led to the discovery of key regulators of the NRF2 pathway, including CAND1, KEAP1, and UBE2M, whose downregulation restored the FUS nucleocytoplasmic ratio. These genes are central to the neddylation pathway, which governs both autophagy and NRF2-driven cellular stress responses. Complete knock-out or dCas9-mediated inhibition of CAND1, KEAP1, and UBE2M in fibroblasts and iPSC-derived neurons activated the NRF2 signaling pathway, boosted autophagy through the KEAP1-NRF2-p62 loop, and rescued nuclear FUS localization."

Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Dementia • Frontotemporal Lobar Degeneration • FUS • UBE2M

The Atpase Domain of LONP1 Is Necessary for Mitochondrial Protein Solubility and the Viability of Acute Myeloid Leukemia (AML) Cells (ASH 2023) - "Bardoxolone methyl (CDDO-Me) is a synthetic triterpenoid that inhibits the ATPase activity of LONP1 by binding to an allosteric site near the ATPase domain of the enzyme...Selective inhibition of this domain leads to mitochondrial protein aggregation, impaired mitochondrial respiration and AML cell death. Thus, inhibiting the ATPase domain of LONP1 may be a novel therapeutic strategy for AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • CD34 • LONP1

Local Activation of Nrf2 Inhibits Arteriovenous Fistula Stenosis in Mice (KIDNEY WEEK 2025) - "However, a single higher dose of either bardoxolone (1 μg/kg) or omaveloxolone (2 μg/kg) was enough to improve patency. Bardoxolone methyl reduced the volume of the stenotic lesion from 0.4 mm 3 to 0.2 mm 3 (Fig 1). Conclusion Our results suggest that local Nrf2 activation at the time of AVF creation potentially improves maturation rates by inhibiting stenosis."

Preclinical • Cardiovascular

The Mitochondrial Unfolded Protein Response (UPRmt) Is Upregulated in Acute Myeloid Leukemia (AML) and Inhibiting the UPRmt Protease, LONP1, Leads to Mitochondrial Protein Aggregation and Cell Death Selectively in AML (ASH 2024) - "Genetic depletion and chemical inhibition (Omaveloxolone and Bardoxolone methyl) of LONP1 increased mitochondrial protein aggregation in AML cell lines and primary AML samples with high LONP1 but not normal cells or AML samples with low LONP1 and low mitochondrial protein import. In summary, a subset of AML patients have increased mitochondrial protein import and upregulate UPRmt as a protective response. Targeting UPRmt and the processing of newly imported mitochondrial proteins at the level of LONP1 leads to increased mitochondrial protein aggregation and cell death in AML while sparing normal hematopoietic cells in vitro and in vivo."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Metabolic Disorders • Oncology • LONP1

Human coronavirus OC43 infection in human cerebral organoids: novel insights on pathogenesis and potential therapeutic interventions. (PubMed, J Biomed Sci) - "Conclusively, HCOs infected with HCoV-OC43 offer valuable insights into the pathogenesis of HCoVs in central nervous system (CNS), and might serve as a tool for developing novel therapeutic strategies for HCoVs infections, including COVID-19, especially on exploring treatment candidates."

Journal • CNS Disorders • Infectious Disease • Inflammation • Novel Coronavirus Disease

Identification and Verification of Immune Metabolism-Related Biomarkers and Immune Infiltration Landscape for Pediatric Opsoclonus Myoclonus Ataxia Syndrome in Neuroblastoma. (PubMed, CNS Neurosci Ther) - "Four immune metabolism-associated diagnostic genes were identified, including TRAF3IP2, RIPK1, KEAP1, and DPP4 for OMAS."

Biomarker • Journal • Ataxia • Movement Disorders • Neuroblastoma • Oncology • Pediatrics • Solid Tumor • KEAP1 • RIPK1 • TRAF3IP2

KEAP1 C151 active site catalysis drives electrophilic signaling to upregulate cytoprotective enzyme expression. (PubMed, Redox Biol) - "NRF2 activators in clinical use and trials (omaveloxolone, bardoxolone methyl, and sulforaphane) readily compete with monobromobimane for C151. Overall, this work suggests enzymatic catalysis is the primary reason that C151 acts as a sensor cysteine for therapeutic, electrophilic NRF2 activators, highly favoring reaction with C151 over other cellular cysteines. The kinetic targeting of electrophiles such as sulforaphane and omaveloxolone to the C151 active site provides an explanation for how electrophilic compounds can be selective pharmacological agents."

Journal • Inflammation • KEAP1

Development of a leucine aminopeptidase-activatable co-prodrug from CDDO-Me and ligustrazine for synergistic treatment of liver injury. (PubMed, Bioorg Chem) - "Furthermore, CHL reduced p-p65 expression by 5-fold, indicating its effective inhibition of NF-κB transcriptional activity and thereby alleviating inflammatory responses. Therefore, the LAP-activable co-prodrug CHL holds promising potential as a candidate for the synergistic treatment of liver injury."

Journal • Hepatology • Inflammation • Liver Cancer • Liver Failure • Oncology • Solid Tumor • NQO1 • RELA

Investigating the Potential of CDDO-Me as an HMGB1 Inhibitor in Mitigating Cerebral Ischemia-Reperfusion Injury. (PubMed, J Neuroimmune Pharmacol) - "Further virtual mutagenesis and binding free energy calculations identified F38 and F89 in the A-box as key residues involved in HMGB1-CDDO-Me interaction. These findings indicated that CDDO-Me can improve stroke-induced inflammatory damage through direct binding HMGB1 and negative regulation of HMGB1-TLR4 downstream cytokine signaling activity."

Journal • Cardiovascular • CNS Disorders • Diabetic Nephropathy • Inflammation • Ischemic stroke • Nephrology • Renal Disease • Reperfusion Injury • HMGB1 • TLR4

Synthesis and Biological Profile of Omaveloxolone: The Cornerstone for Friedreich Ataxia Treatment. (PubMed, Int J Mol Sci) - "Through these mechanisms, OMA contributes to tissue protection and inflammation reduction in patients with FA. The review also highlights future perspective, focusing on the challenges associated with OMA reprofiling through innovative drug delivery approaches and its potential repurposing for diseases beyond FA."

Journal • Review • Ataxia • Friedreich ataxia • Inflammation • Metabolic Disorders • Movement Disorders

Nrf2 signaling in bone health: unlocking new avenues for osteoporosis management. (PubMed, Inflammopharmacology) - "Therapeutic activation of Nrf2 using agents such as bardoxolone methyl, sulforaphane, quercetin, and curcumin shows promise in mitigating bone loss. However, precise modulation is crucial to avoid potential adverse effects. Overall, Nrf2 represents a promising target for the prevention and treatment of OP and related musculoskeletal disorders."

Journal • Review • Inflammation • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatology • NFE2L2

Design and Synthesis of Senescence-Targeted Prodrugs with Senomorphic and Senolytic Properties To Mitigate Chemotherapy-Induced Kidney Injury. (PubMed, J Med Chem) - "Herein, we repurposed an antioxidant agent, bardoxolone methyl (CDDOMe), as a novel senomorphic agent to mitigate the chemotherapy-induced kidney injury and subsequently modified it into a series of senescence-associated β-galactosidase (SA-β-gal) activated prodrugs...Notably, Gal-CDD-01 possesses favorable efficacy and distribution selectivity in vivo, resulting in amelioration of motor functions in mice with kidney injury. Overall, this study presents a rational design for a dual-functional senescence-targeted prodrug and also explores its potential application in treating the chemotherapy-induced kidney injury."

Journal • Renal Disease

Targeting Bach1 and Keap1 to ameliorate oxidative stress-induced pulmonary inflammation and epithelial barrier breakdown (ERS 2025) - "Unlike bardoxolone methyl treatment, not all anti-OS markers were altered in the Bach1 KO mice. And whilst both treatments protected against OS-induced epithelial membrane damage, only bardoxolone treatment inhibited the airway neutrophilia. Keap1 inhibition results to wider Nrf2 pathway activation compared to Bach1 and thus might have a greater potential as a novel therapeutic for chronic lung diseases with an OS burden."

Oxidative stress • Asthma • Chronic Obstructive Pulmonary Disease • Inflammation • Pneumonia • BACH1 • BRIP1 • KEAP1 • NFE2L2

Deciphering the quantitative relationship between NRF2 and SRXN1 through semi-mechanistic computational modeling. (PubMed, Toxicology) - "We developed a semi-mechanistic mathematical model based on time course experimental data of NRF2 and SRXN1 protein expression in HepG2 cells following single or repeated exposure to NRF2 activating soft electrophiles (sulforaphane, andrographolide, ethacrynic acid or CDDO-me) at a wide concentration range. Moreover, this modulation of the transcription factor activity of NRF2 is time-, compound- and exposure scenario specific. We conclude that a complete understanding of NRF2-mediated ARE genes activation requires detailed dynamic information on NRF2 binding partners and cofactors."

Journal

Intensity, Duration, and Context Dependency of the Responses to Nutrient Surplus and Deprivation Signaling in the Heart: Insights Into the Complexities of Cardioprotection. (PubMed, Circulation) - "Nutrient surplus sensing through PI3K (phosphoinositide-3-kinase) and mTOR (mechanistic target of rapamycin) stimulates anabolism to expand cellular mass, whereas nutrient and energy deprivation sensing through SIRT1 (sirtuin-1) and AMPK (adenosine monophosphate-activated protein kinase) promotes catabolism to support cytoprotective quiescence...Sustained activation of PPARγ, NRF2, and HIF-1α in nutrient surplus states can lead to maladaptive ventricular remodeling, thus explaining the results of clinical trials with thiazolidinediones, bardoxolone, and prolyl hydroxylase inhibitors...These observations, considered collectively, suggest that no protein or cellular process viewed in isolation can be regarded as cardioprotective or maladaptive. Cell signals operate usefully if they are delivered as part of an orchestrated program of compartmentalized nuanced bursts, acting as elements of multifaceted oscillating systems whose periodicity is determined by the need to..."

Journal • Review • Cardiomyopathy • Cardiovascular • Genetic Disorders • Obesity • AMPK • HIF1A • HMOX1 • PPARA • SIRT1

Cigarette smoke disrupts osteogenic-adipogenic balance via Nrf2/HERC2 axis-driven ferroptosis. (PubMed, Free Radic Biol Med) - "CS induces bone loss by dysregulating the Nrf2/HERC2 axis, leading to ferroautophagy-driven ferroptosis and impaired osteogenesis. Pharmaceutical Nrf2 activation mitigates these effects, highlighting a novel therapeutic target for smoking-related osteoporosis."

Journal • Osteoporosis • Rheumatology • Targeted Protein Degradation • CTNNB1 • KEAP1 • NCOA4 • UBR5

Bardoxolone methyl improves survival and reduces clinical measures of kidney injury in tumor-bearing mice treated with cisplatin. (PubMed, AAPS Open) - "Cisplatin treatment significantly decreased tumor burden compared to vehicle-treated mice (p < 0.05 after two cisplatin doses) - a response that was not altered by BARD co-treatment. Overall, the results of this study demonstrate that BARD has the potential to improve survival and reduce clinical measures of kidney injury in tumor-bearing mice treated with cisplatin, suggesting it could be used as a nephroprotectant to mitigate cisplatin-induced AKI."

Journal • Preclinical • Acute Kidney Injury • Nephrology • Oncology • Renal Cell Carcinoma • Renal Disease • KIM1

HDAC3 represses Nrf2-GDF11 signaling to drive chondrocyte adipogenesis in temporomandibular joint osteoarthritis. (PubMed, J Adv Res) - "Our findings indicate that aberrant biomechanical force induces HDAC3 upregulation, which suppresses Nrf2-mediated transactivation of GDF11, thereby promoting chondrocyte adipogenesis and exacerbating TMJ OA progression."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology • ACAN • GDF11 • HDAC3 • NFE2L2

Bardoxolone Methyl: A Comprehensive Review of Its Role as a Nrf2 Activator in Anticancer Therapeutic Applications. (PubMed, Pharmaceuticals (Basel)) - "Additionally, bardoxolone methyl modulates mitochondrial function, reduces glycolytic and oxidative phosphorylation capacities, and induces reactive oxygen species (ROS)-mediated stress responses. In this review, we summarize the available literature regarding the studies which investigated the effects of bardoxolone methyl as anticancer agent."

Journal • Review • Brain Cancer • Breast Cancer • Colorectal Cancer • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Genito-urinary Cancer • Glioblastoma • Lung Cancer • Oncology • Oral Cancer • Ovarian Cancer • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • Squamous Cell Carcinoma

CDDO-Me Triggers ROS-Dependent Ferroptosis and Apoptosis in Cervical Cancer via targeting PI3K/Nrf2 pathway. (PubMed, Food Chem Toxicol) - "CDDO-Me induces CC cell lines apoptosis and ferroptosis through the PI3K/Nrf2 signaling pathway, for exerting anti-proliferation effects."

Journal • Cervical Cancer • Oncology • Solid Tumor • GPX4 • NQO1